This invention relates to polypeptides which have the activity of specifically inhibiting epimorphins (hereinafter referred to as epimorphin antagonist activity), substances promoting the morphogenesis of epithelial tissue, and which are useful as the active ingredient of pharmaceuticals.
The normal morphogenesis of epithelial tissue has been suggested to be controlled by factors derived from mesenchymal cells present around the epithelial tissue. Diseases ascribed to the abnormal morphogenesis of epithelial tissue are largely due to abnormalities in mesenchymal cells. These findings have aroused an interest in the clarification of the mechanism by which mesenchymal cells control the morphogenesis of epithelial tissue. However, substances involved in the control of morphogenesis of epithelial tissue are expressed under time and spatial control in a complicated system. It is extremely difficult to isolate these substances and analyze their functions. It is also difficult to construct a model experimental system simplifying the morphogenesis of epithelial tissue. For these and other reasons, much progress has not been made to date in researches in this field. Thus, analysis of the control mechanism for the morphogenesis of epithelial tissue has been demanded keenly in order to elucidate the mechanism of occurrence of diseases associated with the morphogenesis of epithelial tissue and establish methods for treating these diseases.
Under these circumstances, a report was made of success in the isolation of epimorphin taking part in the control of the morphogenesis of epithelial tissue (Japanese Laid-Open Patent Publication No. 25295/94 or European Patent Application Laid-Open Publication No. 562123, hereinafter called EPA562123). This substance was shown to be a physiologically active substance containing a protein of 277 to 289 amino acids as the core protein, and to be biosynthesized mainly by mesenchymal cells. Epimorphin was also shown to have the action of promoting the morphogenesis of epithelial tissue, and it was also indicated that when epimorphin did not function, normal tissue formation did not take place.
As a substance known to inhibit the physiological action of epimorphin (epithelial tissue morphogenesis promoting action), there is an antibody (M-1) which binds specifically to epimorphin, inhibiting its action (Japanese Laid-Open Patent Publication No. 25295/94 or EPA562123; CELL, 69, pp. 471-481, 1992). This antibody is useful for clarifying the mechanism for the normal morphogenesis of epithelial tissue by epimorphin, and is expected to be useful in the elucidation of the mechanism of occurrence of diseases ascribed to the abnormal expression (excessive expression) of epimorphin and in the prevention and treatment of these diseases. Epimorphin also acts to promote the morphogenesis of a hair follicle. Thus, the above-mentioned antibody that inhibits the activity of epimorphin is likely to induce alopecia or inhibit hair growth.
However, this antibody posed the problem of being unstable and becoming easily deactivated during preparation, thus making it difficult to develop or stably supply it as a pharmaceutical or a hair growth inhibitor. Since its molecular weight is large (more than 150,000 Kd), moreover, it was unable to pass through the keratin of the skin easily and was not expected to inhibit hair growth sufficiently. For these reasons, it has been demanded to develop a substance which inhibits the aforementioned activity of epimorphin, and which is stable and has a low molecular weight of, say, less than several thousands permitting its passage through the skin. In particular, epimorphin antagonist, a substance binding to the receptor on an epithelial cell where epimorphin binds, and being capable of inhibiting the epithelial tissue morphogenic activity of epimorphin, is expected to take marked effect in serving as the active ingredient of a pharmaceutical or a hair growth inhibitor, and in elucidating the mechanism of action of epimorphin.
In addition, in removing hair on the arm or leg, it has been customary practice to directly pull it out by means of a tape or forceps, or to apply to the site a solution containing an ingredient such as an alkali for lysis of the hair. The former method causes pain, while the latter method damages the skin. If it is possible to provide a substance acting to inhibit the function of epimorphin and having a molecular weight low enough for percutaneous absorption, therefore, such a substance is expected to be useful as the active ingredient of a hair growth inhibitor that avoids the above problems. That is, hair growth can be suppressed for a long term by applying a substance with such characteristics after shaving. This substance is usable as a hair growth inhibitor which overcomes the drawbacks of a conventional hair remover.
An object of the present invention is to provide a substance for inhibiting the action of epimorphin. More particularly, the invention aims to provide a substance useful as an epimorphin antagonist which specifically inhibits the morphogenic activity of epimorphin on epithelial tissue. Further, the invention aims at providing an epimorphin antagonist having such a characteristic effect, a low molecular weight, and stability.
Another object of the invention is to provide a pharmaceutical which contains as the active ingredient an epimorphin antagonist inhibiting the morphogenic activity of epimorphin on epithelial tissue, and which is useful for the prophylaxis and/or treatment of diseases attributable to the excessive expression of epimorphin.
Still another object of the invention is to provide a hair growth inhibitor which contains as the active ingredient the above-described epimorphin antagonist.